According to the World Health Organization (WHO) it is estimated that mental and neurological diseases affect nearly 700 million people in the world, which represents one third of all cases of non-communicable diseases.
Anxiety disorders are defined by psychic conditions comprising symptoms common to an acute or excessive anxiety setting, which plays a key role in the behavioral and psychological processes of the individual, resulting in losses on his professional and social performance.
According to the Anxiety and Depression Association of America—ADAA, anxiety disorders are the most common mental illnesses in the United States, affecting about 40 million adults above 18 years, i.e. 18% of the population.
In Brazil, the most recent statistical study regarding the prevalence of mental illness is São Paulo Megacity Mental Health Survey, a study conducted in great Sao Paulo sponsored by FAPESP. This study, whose statistics were published in the Oxford Textbook of Community Mental Health (2011 ed., page 55), the incidence of anxiety disorders affects 19.9% of a population, out of 29.6% of individuals who alleged to have been affected by mental disorders within 12 months before the interview.
It is estimated that only one third of individuals affected by any anxiety disorder receive treatment. This low index is caused by factors such as prejudice, fear, incomprehension, lack of information about this mental disturbance and inability to seek assistance due to the condition itself.
According to DSM-IV—Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition, Text Revision) anxiety disorders include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical conditions, substance-induced anxiety disorder and anxiety disorder without specific cause.
Although this manual intends to categorize the various anxiety disorders through descriptive and observable definitions, in practice, these definitions represent only a part of the clinic observed reality. Frequently, health care professionals face health frameworks whose standardization to the disorders described in DSM is inadequate for patients under treatment. This is due to phenomena such as comorbidity and frequent setting of atypical and sub-clinical symptoms.
A collaborative study of the World Health Organization about the psychological problems in general health treatment (“The World Health Organization (WHO) Collaborative Study on Psychological Problems in General Health Care”) pointed out that anxiety and depression disorders are the most frequent co-occurring psychiatric disorders. In this study, among patients diagnosed with anxiety disorder, 45% also had depression disorder, of which 40% also had anxiety disorder.
According to DSM-IV, depression disorders include major depressive disorder or major depression, dysthymic disorder or dysthymia and minor depression. This category also includes atypical mood disorders, whose development occur under special or singular circumstances, which are psychotic depression, postpartum depression, seasonal affective disorder and bipolar disorder.
Two long-term studies indicated the existence of a correlation between anxiety and depression. The study, known as “Munich follow-up Study” (Wittchen H U, Essau C A. Comorbidity of anxiety disorders and depression: does it affect course and outcome? Psychiatry Psychobiol. 1989, 4: 315-323; Lifetime and Six-month Prevalence of Mental Disorders in the Munich Follow-up Study—Eur. Arch. Psychiatry Clin. Neurosci. 1992, 241: 247-258) demonstrated that most individuals with both disorders initially presented pure anxiety diagnosis before depression. This same observation was made in the study known as “Zurich Cohort Study of Young Adults” (Angst J, M Vollrath, Merikangas K R, Ernst c. Comorbidity of anxiety and depression in the Zurich cohort study of young adults. In: Maser J D, Cloninger C R, eds. Comorbidity of Mood and Anxiety Disorders. Washington, D.C.: American Psychiatric Press, 1990: 123-137). These studies also evidenced that individuals originally diagnosed with pure depression tend to remain with this diagnosis. These observations demonstrated that anxiety has a strong correlation with depression, and could trigger it over time.
In general terms, individuals from comorbid anxiety disorders to depression disorders have more severe symptoms, which leads to a more accentuated disability percentage than it is observed in patients with any of these pure disorders. The course of the disease is less favorable in patients with comorbid condition, since the response to antidepressant treatment and remission of symptoms is significantly lower (Medicographia. 2009, 31: 126-131).
Although anxiety disorders are different from depression disorders, people with depression usually develop symptoms similar to anxiety disorders, such as nervousness, irritability, sleeping problems and concentration. Even so, each disorder has its own cause, as well as behavioral and emotional symptoms. Many of the individuals who develop depression showed some history of anxiety disorder in their lives. Although there is no evidence that a disorder causes the other, it is clearly evident that many individuals are affected by both (source: http://www.adaa.org/understanding-anxiety/depression).
In a recent research on the determining factors for the lack of response in patients with treatment-resistant depression, the presence of any comorbid anxiety disorder was the most significant factor associated with this lack of response (Souery D, Oswald P, Massat I, et al; Group for the Study of Resistant Depression. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J. Clin. Psychiatry. 2007, 68: 1062-1070).
Much progress was made on the understanding that the comorbid anxiety disorders to depression disorders are a very common condition. If not treated properly, patients with this comorbidity have a recovery lower than patients with another pure condition, besides of presenting more severe symptoms and in higher number than those observed in patients diagnosed with depression.
Presently, there are several classes of medicines that are used in the treatment of anxiety disorders.
Benzodiazepines for long corresponded to the group of medicines of choice for the treatment of anxiety disorders. Although they are effective in relieving symptoms related to these disorders, this class of medicines triggers tolerance, causes physical dependence and, when the use is interrupted after a long period of time, causes withdrawal syndrome. Due to these disadvantages, this type of medicine is usually prescribed for short periods of time, especially for patients with a history of alcohol abuse or of development of medicine dependence. Examples of medicines belonging to this class are alprazolam, clonazepam, diazepam, lorazepam and oxazepam, among others.
Buspirone is a partial agonist of 5-HT1A receptors which has effect in the treatment of anxiety. Since it acts on the serotonergic system, this medicine is associated with a lower incidence of side effects when compared to benzodiazepines. The time required to establish the anxiolytic effect provided by this medicine is considerably long, from four to six weeks to be effective, which is a disadvantage and restricts its use in cases of emergency. Besides this factor, many clinical professionals do not believe that its effectiveness is comparable to that of benzodiazepines (Uriel Halbreich and Stuart A. Montgomery—Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders—American Psychiatric Press. Ed. 2000, pg. 336).
Many medicines originally developed for treating depression relieved the symptoms observed in anxiety disorders.
Tricyclic antidepressants such as imipramine, desipramime, amitriptyline and clomipramine, among others, were the first medicines developed to treat depression that demonstrated a relieve of symptoms observed in anxiety disorders. The medicines have In common structures comprised by three fused rings, and most of them act as serotonin and norepinephrine reuptake inhibitors, blocking the serotonin transporter and the norepinephrine transporter. They also act on muscarinic receptors of cholinergic system and act as antagonists on histamine receptors H1 and H2. Due to the multiple activity on several receptors and transporters, tricyclic drugs are associated with a wide range of side effects, the most dangerous being those related to cardiac and central nervous systems, in case of overdose. Besides this factor, these medicines also trigger the withdrawal syndrome, requiring a gradual reduction of dose until the complete withdrawal. The withdrawal syndrome caused by this class of medicines includes symptoms such as nausea, vomiting, diaphoresis, unrest, insomnia, headaches, dizziness, runny nose, tremor, chills, weakness, fatigue, musculoskeletal pain, abdominal spasms, malaise, anxiety and irritability, among others (Can. Med. Assoc. J. 1981, 125(5): 420-422).
With the development of modern medicines for the treatment of depression, which target a narrower range of receptors or carriers, these new medicines, considered more selective, occupied the place of the tricyclic antidepressants and also earned their place in the treatment of anxiety disorders.
Among the preferred medicines currently employed the selective serotonin reuptake inhibitors, known as ISRS (or SSRI in English) are worthy to mention. Examples of compounds belonging to this class are paroxetine, fluoxetine, citalopram, escitalopram and sertraline. As buspirone, the therapeutic effect of ISRSs takes between four to six weeks to be reached achieved, which is a disadvantage. These medicines have a smaller range of side effects, the most common of them being weight gain, insomnia and particularly sexual dysfunction. It is estimated that the percentage of patients that develop some kind of sexual dysfunction associated with the use of ISRSs is between 30% to 60% of patients treated (Gregorian R S et al., Ann. Pharmacother., 2002, 36 (10): 1577-1589), an extremely high percentage and that certainly interferes significantly with treatment compliance. Moreover, as in previous cases, the ISRSs also trigger the withdrawal syndrome whose main symptoms are nausea, headaches, electric shock sensations, insomnia, tremor, confusion, nightmares and vertigo, as well as psychological symptoms such as anxiety, unrest, crying, irritability and aggressiveness.
Another class of medicines that have been currently highlighted for treating anxiety is comprised by the serotonin-norepinephrine reuptake inhibitors, known as IRSN (or SNRI in English). This class of medicines includes compounds such as venlafaxine and duloxetine. As dual inhibitors, these medicines act on serotonin norepinephrine reuptake inhibition, being subject to the same side effects and withdrawal syndrome observed for ISRSs. Therapeutically, these medicines act by inhibiting serotonin reuptake when used in low concentration and, when used in high concentrations, they inhibit norepinephrine reuptake.
Agomelatine is an antidepressant that was recently placed on the market. This medication has a mixed action mechanism, acting through the agonism of melatoninergic MT1 and MT2 receptors, and the antagonism of serotonergic 5-HT2C receptors. Although its use is approved for the treatment of depression, some studies indicate potential to be used in the treatment of generalized anxiety disorder (Levitan, N M et al. em Exp. Clin. Psychopharmacol. 2012, 20(6): 504-509 —A review of preliminary observations on agomelatine in the treatment of anxiety disorders).
Although there are several options for treating anxiety disorders, all drugs developed so far present negative features, many of which interfere with its clinical use. Among them, there should be highlighted the trend of benzodiazepines in developing physical dependence, issues related to withdrawal syndrome observed in all classes of medicines mentioned and, when considering the two classes of medicines more employed nowadays for the treatment of anxiety disorders, ISRS and IRSN, besides of the withdrawal syndrome triggered by an abrupt interruption of medication, the use of these inhibitors is associated with a high percentage in triggering some kind of sexual dysfunction, which negatively interferes on patient compliance to treatment.
Among the current possibilities for treating anxiety disorders, the need in developing medicines with greater efficiency and less prone to induce withdrawal syndrome still exists.
Surprisingly, it was found that the compounds of general formula (I), where R1 is —OCH3 or —CN, are potent anxiolytic.

A complementary study conducted with the compound of general formula (I), where R1 is —OCH3, showed that, besides of being anxiolytic, this compound cannot trigger the withdrawal syndrome.